“We were really excited to know that the SVS [Society for Vascular Surgery] is supporting our research,” Sujin Lee (Massachusetts General Hospital, Boston, USA) told Vascular News on receiving the SVS Foundation James S T Yao Resident Research Award for a paper examining the role of the FNDC1 protein in vascular calcification.
Lee presented the paper—“FNDC1 is implicated in small- and large-vessel arterial disease and induces vascular calcification via PI3K/AKT signalling and the nicotinamide adenine dinucleotide [NAD] salvage pathway”—at the2025 Vascular Annual Meeting (VAM; 4–7 June, New Orleans, USA).
The focus of the research project, which Lee noted has spanned more than three years, is the “highly complex and active pathobiological process” that is vascular calcification. Despite its prevalence in vascular surgery patients, Lee highlighted that there are currently no therapies that directly target vascular calcification—a gap in the literature that she and colleagues hope to address.
“The goal of this project was to really understand the mechanisms behind vascular calcification,” Lee said. “We wanted to look at the convergence between small and large vessel calcification to determine the molecular pathways that drive the phenotypic change of vascular smooth muscle cells to bone-like cells.”
To do so, Lee explained that the research team looked at two different models of vascular calcification: calciphylaxis (to model small-vessel disease) and coronary artery disease (to model large-vessel disease).
Lee continued: “We did human transcriptomic studies to look at the differentially expressed transcriptomes and the different pathways that are perturbed in the disease state for both of these disorders of vascular calcification.”
Subsequently, Lee shared that the top 10 upregulated genes in each of the two disease states were validated at the protein level on immunofluorescent staining.
“We were able to narrow down that list to one protein, which is FNDC1, or fibronectin type III domain-containing protein 1,” Lee said, going on to note that knockdown and overexpression experiments using vascular smooth muscle cells demonstrated that FNDC1 was necessary to induce the calcific phenotype switch of smooth muscle cells in vascular calcification. She then looked at the mechanism of action before conducting further network analyses.
Summarising this part of the study, Lee outlined that there are two major pathways that FNDC1 might be activating to induce vascular calcification: the PI3K/AKT signaling pathway and the NAD biosynthesis pathway, “which deals with metabolic reprogramming of the cell.”
Furthermore, Lee noted that the genetic deletion of FNDC1 attenuated aortic calcification and improved survival in two mouse models of vascular calcification. The researchers also found that the administration of a small molecule inhibitor of one of the downstream targets of FNDC1 protected against calcification, which Lee stated are promising results for a potentially new therapy targeting calcification in humans.
Finally, Lee reported that the team conducted a further study using the UK Biobank to assess whether FNDC1 can be used as a biomarker in both calciphylaxis and coronary disease in large human cohort studies. “There were 43,000 patients within the UK Biobank that seemed to have an association between FNDC1 and cardiovascular morbidity and mortality,” Lee revealed.
Beyond the research presented at VAM, Lee detailed that the next step is to “continue to build on our understanding of the mechanisms of vascular calcification and to ultimately develop a therapy.”
The James S T Yao Resident Research Award is intended to motivate physicians early in their training to pursue their interest in research that explores the biology of vascular disease and potential translational therapies.
